The present invention relates to novel thiazolopyrimidine compounds having excellent adenosine A3 receptor antagonistic activity, their production, pharmaceutical compositions comprising them, and the like.
As subtypes of adenosine receptors, A1, A2a, A2b and A3 are known. Adenosine induces bronchial constriction in asthma patients, while theophylline, which is known as an antiasthmatic, antagonizes adenosine. Recently several reports showed that activation of adenosine A3 receptors in rats promotes degranulation of mast cells [Journal of Biological Chemistry, 268, 16887-16890 (1993)], that adenosine A3 receptors exist on peripheral blood eosinophils and that the stimulation of adenosine A3 receptors activates phospholipase C and elevates intracellular calcium concentration [Blood, 88, 3569-3574 (1996)].
Currently, as selective adenosine A3 receptor antagonists, xanthine derivatives are reported in GB-A-2288733 and WO 95/11681, and the following compounds are reported in Journal of Medicinal Chemistry, 40, 2596-2608(1997). 
WO 97/33879 discloses an adenosine A3 receptor antagonist comprising a compound of the formula: 
wherein R is hydrogen, chlorine, bromine, fluorine, iodine, hydroxy, C1-4 alkyl, C1-4 alkoxy or C1-4 alkylcarboxy, or a salt thereof and, specifically discloses 
On the other hand, as for thiazolopyrimidine compounds, the following compounds are reported.
1) As a compound having immunostimulating activity, a compound represented by the formula: 
wherein X is nitrogen atom or R2xe2x80x94C group, R is hydrogen atom, a pharmaceutically acceptable cation or alkyl group (C1-5), R1 and R2 are the same and different and are hydrogen atom, alkyl group (C1-5) or, aralkyl, phenyl, thienyl or pyridyl group optionally substituted with halogen atom, alkyl or alkoxy (the number of carbon atom of alkyl being up to 4) or cycloalkyl group (C1-5), or a pharmaceutically acceptable salt, and specifically, the following compounds. 
(JP 52-148096 A)
2) As a compound having anti-inflammatory activity, a compound represented by the formula: 
wherein (a) Ra together with Rb forms xe2x80x94C(R3)xe2x95x90CHxe2x80x94COxe2x80x94Nxe2x95x90 or (b) Ra is hydrogen atom and Rb is xe2x95x90Nxe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94NR7R8, R1, R2 and R3 are the same or different, and are hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-7 carbonylalkoxy or phenyl, or R3 is as defined above and R1 together with R2 forms phenyl optionally substituted with two C1-6 alkyls, C1-6 alkoxys, C2-7 carbonylalkoxys, and R7 and R8 are independently hydrogen atom or C1-6 alkyl, or they together with the adjacent nitrogen atom form pyrrolidino, piperidino or homopiperidino, and, the following specific compound: 
(GB 1345148)
3) As agrochemicals, 
(Journal of Agricultural and Food Chemistry, 39 (12), 2300-2303 (1991))
4) 
(Journal fxc3xcr Praktische Chemie, 330 (4) 607-616 (1991))
5) 
(Indian Journal of Chemistry, Section B, 23 B (2), 117-120 (1984))
6) 
(Heterocyclics, 20 (6), 1089-1097 (1983))
7) As a compound having anti-microbial activity, 
(Journal of Pharmaceutical Sciences, 62 (11), 1785-1789 (1973))
It is thought that adenosine causes asthma through its binding to an adenosine A3 receptor, therefore A3 adenosine receptor antagonists are expected to become a new type of anti-asthma drug and the like. Accordingly, an agent for antagonizing adenosine at adenosine A3 receptors which has potent antagonistic activity, good oral absorption and good metabolical stability are expected to have potent therapeutic effects for asthma, inflammation, Addison""s diseases, autoimmune hemolytic anemia, Crohn""s diseases, psoriasis, rheumatism, central nerve diseases (e.g., cerebrovacular disorders such as haemorrhagia cerebri, cerebral infarction, etc., head injury, spinal injury, cerebral edema, etc.), diabetes and the like. However, as a prophylactic and therapeutic agent for adenosine A3 receptor-related diseases, no good agent for antagonising adenosine at adenosine A3 receptors are known in terms of potency, safety, bioavailability, metabolic stability, and the like. Therefore, a good agent for antagonising adenosine at adenosine A3 receptors is expected to be developed.
As a result of the present inventors"" intensive study, a compound represented by the formula (I): 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and R1 is an optionally substituted cyclic group, or a salt thereof [hereinafter sometimes abbreviated to compound (I)], whose chemical structure is characterized in that the 2-position of the thiazolopyrimidine ring is substituted with an optionally substituted cyclic group and the 3-position thereof is substituted with an optionally substituted benzene ring, has been synthesized for the first time, and it has been found that the resultant compound (I) has an unexpected, excellent selective affinity to adenosine A3 receptor and antagonistic activity at an adenosine A3 receptor and high stability suitable for a medicine, due to its specific chemical structure, and it is therefore satisfactory as a medicine. Further, the present inventors have also found that a compound represented by the formula (Ia): 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and ring D may further be substituted, provided that the, when the 5-position of the thiazolopyrimidine ring (ring B) is substituted by amino, the 2 position thereof (ring D) is substituted, or a salt thereof [hereinafter sometimes abbreviated to compound (Ia)] including compound (I) has an unexpected, excellent selective affinity to adenosine A3 receptor and antagonistic activity at an adenosine A3 receptor. On the basis of these findings, the inventors have completed the present invention.
That is, the present invention relates to:
1. A compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may be further substituted, and R1 is an optionally substituted cyclic group, or a salt thereof;
2. The compound according to the above 1, wherein ring A is benzene ring which may have 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) carboxy C1-6 alkyl, (viii) carboxy C2-6 alkenyl, (ix) optionally halogenated C2-6 alkynyl, (x) optionally halogenated C3-6 cycloalkyl, (xi) C6-14 aryl, (xii) optionally halogenated C1-6 alkoxy, (xiii) C1-6 alkoxy-carbonyl-C1-6 alkoxy, (xiv) hydroxy, (xv) C6-14 aryloxy, (xvi) C7-16 aralkyloxy, (xvii) mercapto, (xviii) optionally halogenated C1-6 alkylthio, (xix) C6-14 arylthio, (xx) C7-16 aralkylthio, (xxi) amino, (xxii) mono-C1-6 alkylamino, (xxiii) mono-C6-14 arylamino, (xxiv) mono-C7-16 aralkylamino, (xxv) di-C7-16 aralkylamino, (xxvi) di-C1-6 alkylamino, (xxvii) di-C6-14 arylamino, (xxviii) formyl, (xxix) carboxy, (xxx) C1-6 alkyl-carbonyl, (xxxi) C3-6 cycloalkyl-carbonyl, (xxxii) C1-6 alkoxy-carbonyl, (xxxiii) C6-14 aryl-carbonyl, (xxxiv) C7-16 aralkyl-carbonyl, (xxxv) C6-14 aryloxy-carbonyl, (xxxvi) C7-16 aralkyloxy-carbonyl, (xxxvii) 5- or 6-membered heterocyclic-carbonyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxviii) carbamoyl, (xxxix) thiocarbamoyl, (xxxx) mono-C1-6 alkyl-carbamoyl, (xxxxi) di-C1-6 alkyl-carbamoyl, (xxxxii) C6-14 aryl-carbamoyl, (xxxxiii) 5- or 6-membered heterocyclic-carbamoyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxxiv) C1-6 alkylsulfonyl, (xxxxv) C6-14 arylsulfonyl, (xxxxvi) formylamino, (xxxxvii) C1-6 alkyl-carbonylamino, (xxxxviii) C6-14 aryl-carbonylamino, (xxxxix) C1-6 alkoxy-carbonylamino, (xxxxx) C1-6 alkylsulfonylamino, (xxxxxi) C6-14 arylsulfonylamino, (xxxxxii) C1-6 alkyl-carbonyloxy, (xxxxxiii) C6-14 aryl-carbonyloxy, (xxxxxiv) C1-6 alkoxy-carbonyloxy, (xxxxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxxxvii) C6-14 aryl-carbamoyloxy, (xxxxxviii) nicotinoyloxy, (xxxxxix) 5- to 7-membered saturated cyclic amino which may be substituted by a substituent selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and oxo, (xxxxxx) 5- to 10-membered aromatic heterocyclic group which contains, in addition to carbon atoms, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and (xxxxxxi) sulfo (hereinafter referred to as C group-substituents), ring B may further have 1 or 2 substituents selected from the C group substituents, and R1 is C3-6 cycloalkyl group, C1-14 aryl group or a monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring which contains, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, each of which may have 1 to 5 substituents selected from the C group substituents;
3. The compound according to the above 2, wherein R1 is a monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring which contains, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and which may have 1 to 5 substituents selected from the C group substituents as defined in the above 2;
4. The compound according to the above 2 or 3, wherein the 5- to 14-membered heterocyclic ring is (i) 5- to 14-membered aromatic heterocyclic ring selected from the group consisting of thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan and phenoxazine, or a ring formed by this ring fused to one or two benzene rings, (ii) 5- to 10-membered aliphatic heterocyclic ring selected from the group consisting of pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole and dithiazole, or (iii) 7- to 10-membered bridged heterocyclic ring selected from the group consisting of quinuclidine and 7-azabicyclo[2.2.1]heptane;
5. The compound according to the above 2 or 3, wherein the monovalent group formed by removing any one hydrogen atom from the 5- to 14-membered heterocyclic ring is 5- to 14-membered nitrogen-containing aromatic heterocyclic group which contains, in addition to carbon atom(s), 1 to 4 hetero atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom;
6. The compound according to the above 2 or 3, wherein the monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 3-pyrrolyl group, 2-imidazolyl group, 3-pyridazinyl group, 3-isothiazolyl group, 3-isoxazolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group or 2-benzothiazolyl group;
7. The compound according to the above 2 or 3, wherein the monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring is 5- or 6-membered nitrogen-containing aromatic heterocyclic group which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom;
8. The compound according to the above 2 or 3, wherein the monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 3-pyrrolyl group, 3-pyridazinyl group, 3-isothiazolyl group or 3-isoxazolyl group.
9. The compound according to the above 2 or 3, wherein the monovalent group formed by removing any one hydrogen atom from 5- to 14-membered heterocyclic ring is pyridyl group;
10. The compound according to the above 1, wherein R1 is 4-pyridyl group;
11. The compound according to the above 1, wherein R1 is an optionally substituted nitrogen-containing aromatic heterocyclic group;
12. The compound according to the above 1, wherein ring A is benzene ring which may be substituted with C1-6 alkoxy, or one or two C1-6 alkyls;
13. The compound according to the above 1, wherein ring A is benzene ring which may be substituted with C1-6 alkoxy;
14. The compound according to the above 1, wherein the substituent by which ring B may further be substituted is amino;
15. The compound according to the above 1, wherein ring A is benzene ring which may be substituted with C1-6 alkoxy, or one or two C1-6 alkyls, ring B may further be substituted with amino and R1 is pyridyl group;
16. The compound according to the above 1, wherein ring A is benzene ring which may be substituted with C1-6 alkoxy, ring B may further be substituted with amino and R1 is pyridyl group;
17. The compound according to the above 1 which is represented by the formula: 
wherein R2 and R3 are the same or different, and are hydrogen atom or a substituent selected from the C group substituents, and ring A and R1 are as defined in the above 1, or a salt thereof;
18. The compound according to the above 17, wherein R3 is hydrogen atom;
19. (1) 5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one or its salt, (2) 5-amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one or its salt, or (3) 5-amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one or its salt;
20. A prodrug of the compound according to the above 1;
21. A process for producing the compound according to the above 1 or a salt thereof which comprises reacting a compound represented by the formula: 
wherein each symbol is as defined above 1, or its salt, with a compound represented by the formula:
R2xe2x80x94Cxe2x89xa1Cxe2x80x94COOH
wherein R2 is as defined in the above 1, or its salt or reactive derivative, or a compound represented by the formula:
NCCHR3COOH
wherein R3 is as defined in the above 1, or its salt or reactive derivative;
22. A pharmaceutical composition comprising a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and R1 is an optionally substituted cyclic group, or a salt or a prodrug thereof;
23. The composition according to the above 22 which is an adenosine A3 receptor antagonist;
24. The composition according to the above 22 which is an agent for preventing and/or treating diseases related to adenosine A3 receptors;
25. The composition according to the above 22 which is an agent for preventing and/or treating asthma or allergic disease;
26. The composition according to the above 22 which is an agent for preventing and/or treating cerebrovascular disorders;
27. The composition according to the above 22 which is an agent for preventing and/or treating head injury;
28. The composition according to the above 22 which is an agent for preventing and/or treating cerebral edema;
29. An adenosine A3 receptor antagonist comprising a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and ring D may further be substituted, provided that, when the 5-position of thiazolopyrimidine ring is substituted with amino, the 2-position thereof is substituted, or a salt thereof;
30. The antagonist according to the above 29, wherein ring A is benzene ring which may have 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C1-6 alkyl, (vi) optionally halogenated C2-6 alkenyl, (vii) carboxy C1-6 alkyl, (viii) carboxy C2-6 alkenyl, (ix) optionally halogenated C2-6 alkynyl, (x) optionally halogenated C3-6 cycloalkyl, (xi) C6-14 aryl, (xii) optionally halogenated C1-6 alkoxy, (xiii) C1-6 alkoxy-carbonyl-C1-6 alkoxy, (xiv) hydroxy, (xv) C6-14 aryloxy, (xvi) C7-16 aralkyloxy, (xvii) mercapto, (xviii) optionally halogenated C1-6 alkylthio, (xix) C6-14 arylthio, (xx) C7-16 aralkylthio, (xxi) amino, (xxii) mono-C1-6 alkylamino, (xxiii) mono-C6-14 arylamino, (xxiv) mono-C7-16 aralkylamino, (xxv) di-C7-16 aralkylamino, (xxvi) di-C1-6 alkylamino, (xxvii) di-C6-14 arylamino, (xxviii) formyl, (xxix) carboxy, (xxx) C1-6 alkyl-carbonyl, (xxxi) C3-6 cycloalkyl-carbonyl, (xxxii) C1-6 alkoxy-carbonyl, (xxxiii) C6-14 aryl-carbonyl, (xxxiv) C7-16 aralkyl-carbonyl, (xxxv) C6-14 aryloxy-carbonyl, (xxxvi) C7-16 aralkyloxy-carbonyl, (xxxvii) 5- or 6-membered heterocyclic-carbonyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxviii) carbamoyl, (xxxix) thiocarbamoyl, (xxxx) mono-C1-6 alkyl-carbamoyl, (xxxxi) di-C1-6 alkyl-carbamoyl, (xxxxii) C6-14 aryl-carbamoyl, (xxxxiii) 5- or 6-membered heterocyclic-carbamoyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxxiv) C1-6 alkylsulfonyl, (xxxxv) C6-14 arylsulfonyl, (xxxxvi) formylamino, (xxxxvii) C1-6 alkyl-carbonylamino, (xxxxviii) C6-14 aryl-carbonylamino, (xxxxix) C1-6 alkoxy-carbonylamino, (xxxxx) C1-6 alkylsulfonylamino, (xxxxxi) C6-14 arylsulfonylamino, (xxxxxii) C1-6 alkyl-carbonyloxy, (xxxxxiii) C6-14 aryl-carbonyloxy, (xxxxxiv) C1-6 alkoxy-carbonyloxy, (xxxxxv) mono-C1-6 alkyl-carbamoyloxy, (xxxxxvi) di-C1-6 alkyl-carbamoyloxy, (xxxxxvii) C6-14 aryl-carbamoyloxy, (xxxxxviii) nicotinoyloxy, (xxxxxix) 5- to 7-membered saturated cyclic amino which may be substituted by a substituent selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and oxo, (xxxxxx) 5- to 10-membered aromatic heterocyclic group which contains, in addition to one nitrogen atom and carbon atoms, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and (xxxxxxi) sulfo (hereinafter referred to as C group substituents),
ring B may further have 1 or 2 substituents selected from the C group substituents, and
ring D may further have a substituent selected from the C group substituents;
31. A method for antagonizing adenosine A3 receptors which comprises administrating to a mammal an effective amount of a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and ring D may further be substituted, provided that, when the 5-position of thiazolopyrimidine ring is substituted with amino, the 2-position thereof is substituted, or its salt or its prodrug;
32. A method for preventing and/or treating asthma, allergic disease, cerebrovascular disorders, head injury or cerebral edema which comprises administrating to a mammal an effective amount of a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, is ring B may further be substituted, and R1 is an optionally substituted cyclic group, or its salt or its prodrug;
33. Use of a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and ring D may further be substituted, provided that, when the 5-position of thiazolopyrimidine ring is substituted with amino, the 2-position thereof is substituted, or its salt or its prodrug, for manufacturing an adenosine A3 receptor antagonist; and
34. Use of a compound represented by the formula: 
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and R1 is an optionally substituted cyclic ring, or its salt or its prodrug, for manufacturing an agent for preventing and/or treating asthma, allergic disease, cerebrovascular disorders, head injury or cerebral edema.
Further, the present invention relates to:
35. A compound represented by the formula: 
wherein R3 is a substituent, ring A is an optionally substituted benzene ring, and R1 is an optionally substituted cyclic group, or a salt thereof; and
36. An adenosine A3 receptor antagonist comprising a compound represented by the formula: 
wherein R3 is a substituent, ring A is an optionally substituted benzene ring, and ring D may further be substituted, or a salt thereof.
In the above formulas, ring A is an optionally substituted benzene ring.
Examples of the optional xe2x80x9csubstituentxe2x80x9d of ring A include halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.) nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 alkenyl, carboxy C1-6 alkyl (e.g., carboxymethyl, carboxyethyl, etc.), carboxy C2-6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.), optionally halogenated C2-6 alkynyl, optionally halogenated C3-6 cycloalkyl, C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), optionally halogenated C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy (e.g., ethoxycarbonylmethyloxy, etc.), hydroxy, C6-14 aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.), C7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy, etc.), mercapto, optionally halogenated C1-6 alkylthio, C6-14 arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), C7-16 aralkylthio (e.g., benzylthio, phenethylthio, etc.), amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, etc.), mono-C6-14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), mono-C7-16 aralkylamino (e.g., benzylamino, phenethylamino, etc.), di-C7-16 aralkylamino (e.g., dibenzylamino, diphenethylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, etc.), di-C6-14 arylamino (e.g., diphenylamino, etc.), formyl, carboxy, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C3-6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), C6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic-carbonyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, thiocarbamoyl, mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocyclic-carbamoyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), formylamino, C1-6 alkyl-carbonylamino (e.g., acetylamino, etc.), C6-14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), C1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), C6-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ehtylcarbamoyloxy, etc.), di-C1-6 alkyl-carbamoyloxy (dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, 5- to 7-membered saturated cyclic amino which may be substituted, 5- to 10-membered aromatic heterocyclic group which contains, in addition to carbon atoms, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), sulfo and the like (hereinafter sometimes referred to as C group substituents).
Ring A may have 1 to 5, preferably 1 to 3, more preferably 1 or 2 substituents as mentioned above at possible positions thereof and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.). Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
The above-mentioned xe2x80x9coptionally halogenated C2-6 alkenylxe2x80x9d includes, for example, C2-6 alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like.
The above-mentioned xe2x80x9coptionally halogenated C2-6 alkynylxe2x80x9d includes, for example, C2-6 alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), and the like.
The above-mentioned xe2x80x9coptionally halogenated C3-6 cycloalkylxe2x80x9d includes, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.). Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkoxyxe2x80x9d includes, for example, C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.). Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc., and preferably methoxy, etc.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylthioxe2x80x9d includes, for example, C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.). Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.
The above-mentioned xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d of the xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d includes, for example, 5- to 7-membered saturated cyclic amino optionally containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom. Specific examples thereof include pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, tetrahydroazepin-1-yl, etc.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d include, for example, 1 to 3 substituents selected from the group consisting of C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), and 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b] furanyl, etc.), oxo, and the like.
Among the above substituents, optionally halogenated C1-6 alkoxy and one or two optionally halogenated C1-6 alkyls are preferred. In particular, C1-6 alkoxy and one to two C1-6 alkyls are preferred, with two methyls, one tert-butyl, one methoxy, etc. being most preferred.
In the above formulas, ring B may further be substituted.
The optional xe2x80x9csubstituent(s)xe2x80x9d of ring B are, for example, the same as the optional substituent(s) of ring C (the C group substituents) and the like.
As the optional xe2x80x9csubstituent(s)xe2x80x9d of ring B, among others, preferred are groups other than C1-6 alkoxy-carbonyl, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.) nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 alkenyl, carboxy C2-6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.), optionally halogenated C2-6 alkynyl, optionally halogenated C3-6 cycloalkyl, C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), optionally halogenated C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy (e.g., ethoxycarbonylmethyloxy, etc.), hydroxy, C6-14 aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.), C7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy, etc.), mercapto, optionally halogenated C1-6 alkylthio, C6-14 arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), C7-16 aralkylthio (e.g., benzylthio, phenethylthio, etc.), amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, etc.), mono-C6-14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, etc.), di-C6-14 arylamino (e.g., diphenylamino, etc.), mono-C7-16 aralkylamino (e.g., benzylamino, phenethylamino, etc.), di-C7-16 aralkylamino (e.g., dibenzylamino, diphenethylamino, etc.), formyl, carboxy, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C3-6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), C6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic-carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, thiocarbamoyl, mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocyclic-carbamoyl (e:g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), formylamino, C1-6 alkyl-carbonylamino (e.g., acetylamino, etc.), C6-14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), C1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), C6-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-6 alkyl-carbamoyloxy (dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, 5- to 7-membered saturated cyclic amino which may be substituted, 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), sulfo and the like. In particular, amino and the like are preferred.
Ring B may have 1 or 2 substituents as mentioned above at possible positions thereof (5- or 6-position)), preferable one substituent at 5-position, and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
In addition, the substituents at 5- and 6-position of ring B in the compounds (I) and (Ia) can be indicated as R2 and R3, respectively, as follows. 
R2 and R3 may be any groups which can be present at 5-and 6-positions, respectively, and preferred examples include hydrogen atom and the like, in addition to the above-mentioned substituents of ring B. In particular, preferred R3 is hydrogen atom and, as R2, amino group is preferred.
In the above formulas, R1 is a cyclic group which may be substituted.
The xe2x80x9ccyclic groupxe2x80x9d of the xe2x80x9ccyclic group which may be substitutedxe2x80x9d includes, for example, a cyclic hydrocarbon group, a heterocyclic group and the like.
Examples of the above-mentioned xe2x80x9ccyclic hydrocarbon groupxe2x80x9d include cycloalkyl group, aryl group and the like. Among them, a cyclic hydrocarbon group having 1 to 16 carbon atoms is preferred.
As xe2x80x9ccycloalkyl groupxe2x80x9d, for example, C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like are preferred.
As xe2x80x9caryl groupxe2x80x9d, for example, C6-14 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.) and the like are preferred.
As the above-mentioned xe2x80x9cheterocyclic groupxe2x80x9d, there are, for example, a monovalent group formed by removing an optional hydrogen atom from a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, preferably, (i) a 5- to 14-membered, preferably, 5- to 10-membered aromatic heterocyclic ring, (ii) a 5- to 10-membered aliphatic heterocyclic ring and (iii) a 7- to 10-membered bridged heterocyclic ring, etc.
The above-mentioned xe2x80x9c5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic ringxe2x80x9d includes, for example, an aromatic heterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, etc.; and a ring as formed through condensation of those rings (preferably a monocyclic ring) with one or more (preferably one or two) aromatic rings (e.g., benzene ring, etc.), etc.
The above-mentioned xe2x80x9c5- to 10-membered aliphatic heterocyclic ringxe2x80x9d includes, for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, oxathiazole, thiadiazoline, triazoline, thiadiazole, dithiazole, etc.
The above-mentioned xe2x80x9c7- to 10-membered bridged heterocyclic ringxe2x80x9d includes, for example, quinuclidine, 7-azabicyclo[2.2.1]heptane, etc.
Preferable examples of the xe2x80x9cheterocyclic groupxe2x80x9d include, for example, a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, etc.).
When the heterocyclic group contains nitrogen atom (N) or sulfur atom (S), N or S may be oxidized (N-oxide, S-oxide).
Among these groups, a nitrogen-containing 5- or 6-membered aromatic heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, etc.) and the like are preferred. For example, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, in particular, 4-pyridyl, etc.) and the like are more preferred.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9ccyclic group which may be substitutedxe2x80x9d are the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of ring A.
The xe2x80x9ccyclic groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the cyclic group and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
Further, for R1, a basic group is preferred. As a basic group, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), in particular, 4-pyridyl is preferred.
In the above formula, ring D may further be substituted.
The further optional xe2x80x9csubstituent(s)xe2x80x9d of ring D are the same as those mentioned above for the optional substituent(s) of ring A (C group substituents). Preferably, the further optional substituent is the above R1.
Preferred Example of Compound (Ia) is Compound (I).
Preferred example of compound (I) is that wherein R1 is a nitrogen-containing aromatic heterocyclic group which may be substituted and ring B may have substituent(s) other than C1-6 alkoxy-carbonyl.
More specifically, the followings are preferably used as compound (I):
(1) compound (I) wherein ring A is benzene ring which may be substituted with C1-6 alkoxy or one or two C1-6 alkyl, ring B may further have amino and R1 is pyridyl group, or a salt thereof;
(2) compound (I) wherein ring A is benzene ring which may be substituted with C1-6 alkoxy, ring B may further have amino and R1 is pyridyl group, or a salt thereof;
(3) 1) 5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one, 2) 5-amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one, 3) 5-amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one, or a salt thereof;
(4) 5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one or a salt thereof.
Salts of compound (I) and compound (Ia) include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Preferred examples of metal salts include alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts; aluminum salts, etc. Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. Preferred examples of salts with inorganic acids include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc. Preferred examples of salts with organic acids include formates, acetates, trifluoroacetates, phthalate, fumarates, oxalates, tartarates, maleates, citrates, succinates, malates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Preferred examples of salts with acidic amino acids include aspartates, glutamates, etc.
Among others, more preferred are pharmaceutically acceptable salts. For example, for the compound having an acidic functional group in the molecule, mentioned are their inorganic salts, such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), and alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc.; and for the compound having a basic functional group in the molecule, mentioned are their salts with inorganic acids such as hydrobromides, nitrates, sulfates, phosphates, etc., and with organic acids such as acetates, phthalates, oxalates, tartarates, maleates, citrate, succinates, methanesulfonates, p-toluenesulfonates, etc.
Processes for Producing Compound (I) are Mentioned Below.
Compound (I) can be produced by reacting a compound represented by the formula: 
wherein each symbol is as defined above, or a salt thereof with a compound represented by the formula:
R2xe2x80x94Cxe2x89xa1Cxe2x80x94COOH
wherein R2 is as defined above, or a salt thereof or a reactive derivative thereof, or a compound represented by the formula:
NCCHR3COOH
wherein R3 is as defined above, or a salt thereof or a reactive derivative thereof.
Examples of the reactive derivative to be used include a compound whose carboxyl group is esterified with C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C6-10 aryl (e.g., phenyl, naphthyl, etc.), etc., an acid halide such as an acid chloride, an acid anhydride, and the like.
More specifically, compound (I) can be obtained by, for example, a process represented by the following Scheme 1 or its modification or, for example, modification of the process described in Journal of Heterocyclic Chemistry, Vol. 25, pp. 949-953 (1988); ibid., Vol. 28, pp. 489-492 (1991); JP 52-148096 A or GB 1345148; or the like.
In the following Scheme 1, Rxe2x80x2 and Rxe2x80x3 is hydrogen atom, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.) or C6-10 aryl (e.g., phenyl, naphthyl, etc.) and other symbols are as defined above. The compounds in the Scheme also include those in the form of salts and examples of the salts include the same salts as those exemplified with respect to compound (I) and the like.

Compound (II) can be obtained by a per se known process, for example, that described in JP 60-58981 A, JP 61-10580 A, JP 7-503023 A, WO 93/15071, DE-A-3601411, JP 5-70446 A or the like, or its modification.
Compounds (III) and (IV) can be used commercial sources if they are commercially available or can be produced in any per se known process.
Compound (I) is obtained by subjecting compound (II) to condensation with an acetylenecarboxylic acid (III) or its reactive derivative, if desired, in the presence of an acid or a base.
The amount of compound (III) to be used is about 0.5 to about 3.0 mols, preferably about 0.8 to about 2.0 mols, relative to one mol of compound (II).
The amount of the acid or base to be used is about 1.0 to about 30 mols, preferably about 1.0 to about 10 mols, relative to one mol of compound (II).
The xe2x80x9cacidxe2x80x9d includes, for example, phosphoric acids such as polyphosphoric acid, etc.; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, etc.; organic acids such as acetic acid, etc.; mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.; and the like.
The xe2x80x9cbasexe2x80x9d includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, is potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; and the like.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Examples of the solvent to be used include halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, polyphosphoric acids, organic acids, water, and mixtures of two or more of those solvents.
The reaction temperature is generally about xe2x88x925 to about 200xc2x0 C., preferably about 5 to about 150xc2x0 C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.
The product can be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
In addition, compound (I) is obtained by subjecting compound (II) to condensation with a cyanoacetic acid (IV) or its reactive derivative, if desired, in the presence of an acid or a base.
The amount of compound (IV) to be used is about 0.5 to about 3.0 mols, preferably about 0.8 to about 2.0 mols, relative to one mol of compound (II).
The amount of the acid or base to be used is about 1.0 to about 30 mols, preferably about 1.0 to about 10 mols, relative to one mol of compound (II).
The xe2x80x9cacidxe2x80x9d includes, for example, phosphoric acids such as polyphosphoric acid, etc.; organic acids such as acetic acid, etc.; and the like.
The xe2x80x9cbasexe2x80x9d includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; and the like.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Examples of the solvent to be used include halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, polyphosphoric acids, organic acids, water, and mixtures of two or more of those solvents.
The reaction temperature is generally about xe2x88x925 to about 200xc2x0 C., preferably about 5 to about 150xc2x0 C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.
The product can be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Further, as shown by the following Scheme 2, compound (I) can be obtained from compound (V) and a metal cyanide compound (VI). 
wherein L is a leaving group, M is a metal and other symbols are as defined above.
Examples of the leaving group as L include halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-5 alkylsulfonyloxy which may be halogenated (e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), C6-14 arylsulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy, etc.), and the like.
Examples of the metal as M include sodium, potassium, copper, and the like.
The compounds in the Scheme also include those in the form of salts and examples of the salts include the same as those exemplified with respect to compound (I).
Compound (V) can be obtained by a per se known process, for example, that described in JP 60-58981 A, JP 61-10580 A, JP 7-503023 A, WO 93/15071, DE-A-3601411, JP 5-70446 A or the like, or its modification.
Compound (VI) can be used commercial sources if they are commercially available or can be produced in any per se known process.
The amount of compound (VI) to be used is about 0.5 to about 5.0 mols, preferably about 0.8 to about 3.0 mols, relative to one mol of compound (IV).
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Examples of the solvent to be used include ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitrites, sulfoxides, ketones, aromatic amines, alcohols, water, and mixtures of two or more of those solvents.
The reaction temperature is generally about xe2x88x925 to about 200xc2x0 C., preferably about 5 to about 50xc2x0 C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 15 hours.
The product can be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
In the above-mentioned reactions where the starting compounds are substituted by any of amino, carboxy or hydroxy, those groups may be protected by ordinary protective groups which are generally used in peptide chemistry. The protective groups may be removed after the reaction to give the desired products.
The amino-protecting group includes, for example, formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted, phenylcarbonyl which may be substituted, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.) which may be substituted, phenyloxycarbonyl which may be substituted, C7-10 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may be substituted, trityl which may be substituted, phthaloyl which may be substituted, etc. These substituents include, for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, etc. The number of those substituents is 1 to 3.
The carboxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may be substituted, phenyl which may be substituted, trityl which may be substituted, silyl which may be substituted, etc. These substituents includes, for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, butylcarbonyl, etc.), nitro, C1-6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C6-10 aryl (e.g., phenyl, naphthyl, etc.), etc. The number of those substituents is 1 to 3.
The hydroxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may be substituted, phenyl which may be substituted, C7-11 aralkyl (e.g., benzyl, etc.) which may be substituted, formyl which may be substituted, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted, phenyloxycarbonyl which may be substituted, C7-11 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, silyl which may be substituted, etc. Those substituents include, for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C7-11 aralkyl (e.g., benzyl, etc.), C6-10 aryl (e.g., phenyl, naphthyl, etc.), nitro, etc. The number of those substituents is 1 to 4.
Those protective groups may be removed by any per se known methods or analogous methods thereto, such as treatment with acids, bases, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.; and reduction, etc.
In any case, if desired, products formed in the reaction mixtures may further be subjected to deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, chain extension, substituents-exchange reaction and combined reactions thereof, to obtain compound (I). These methods include, for example, the methods described in xe2x80x9cShin Jikken Kagaku Kouza (New Edition of Lectures of Experimental Chemistry)xe2x80x9d 14, 15 (1977) edited by Maruzen.
The above xe2x80x9calcoholsxe2x80x9d include, for example, methanol, ethanol, propanol, isopropanol, tert-butanol, etc.
The above xe2x80x9cethersxe2x80x9d include, for example, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
The above xe2x80x9chalogenated hydrocarbonsxe2x80x9d include, for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
The above xe2x80x9caliphatic hydrocarbonsxe2x80x9d include, for example, hexane, pentane, cyclohexane, etc.
The above xe2x80x9caromatic hydrocarbonsxe2x80x9d include, for example, benzene, toluene, xylene, chlorobenzene, etc.
The above xe2x80x9caromatic aminesxe2x80x9d include, for example, pyridine, lutidine, quinoline, etc.
The above xe2x80x9camidesxe2x80x9d include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.
The above xe2x80x9cketonesxe2x80x9d include, for example, acetone, methyl ethyl ketone, etc.
The above xe2x80x9csulfoxidesxe2x80x9d include, for example, dimethylsulfoxide, etc.
The above xe2x80x9cnitrilesxe2x80x9d include, for example, acetonitrile, propionitrile, etc.
The above xe2x80x9corganic acidsxe2x80x9d include, for example, acetic acid, propionic acid, trifluoroacetic acid, etc.
Where the products are formed in their free form in the above reaction, they may be converted into their salts in any ordinary manner. Where they are formed in the form of their salts, they may be converted into free forms or other salts in any ordinary manner. The thus-obtained compound (I) may be isolated and purified from the reaction mixtures through any ordinary means of, for example, trans-salvation, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like.
Compound (Ia) other than compound (I) can be produced by the process for producing compound (I) or a per se known process or their modified processes.
Where compounds (I) and (Ia) exist in the form of their configurational isomers, diastereomers, conformers or the like, they may be optionally isolated into single isomers through the separation and isolation means mentioned above. Where compounds (I) and (Ia) are in the form of its racemates, they may be separated into Sxe2x80x94 and Rxe2x80x94 forms through any ordinary optical resolution.
Where compounds (I) and (Ia) exist in the form of stereoisomers or tautomers, both single isomers and mixtures of different isomers are included within the scope of the present invention. For example, when compound (I) have amino group at 5-position of the thiazolopyrimidine ring, a compound represented by the formula: 
wherein each symbol is as defined above, is included in the scope of compound (I) of the present invention.
Similarly, when compound (Ia) have amino group at 5-position of the thiazolopyrimidine ring, a compound represented by the formula: 
where each symbol is as defined above, is included in the scope of compound (Ia) of the present invention.
Specifically, the followings are used as compound (Ixe2x80x2) or compound (Iaxe2x80x2):
1) 5-imino-3-(4-metoxyphenyl)-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one, 2) 5-imino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one, 3) 5-imino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one, and the like.
Further, compounds (I) and (Ia) may be in any form of their hydrates and non-hydrates.
Prodrugs of compounds (I) and (Ia) mean compounds that are converted into compounds (I) and (Ia) by a reaction with an enzyme, gastric acid, or the like under a physiological condition in a living body, namely, compounds that are converted into compounds (I) and (Ia) by an enzymatic oxidation, reduction, hydrolysis, or the like or compounds that are converted into compound (I) and (Ia) by hydrolysis with gastric acid or the like. Examples of the prodrug of compound (I) or (Ia) include a compound where the amino group in a compound (I) or (Ia) is acylated, alkylated, or phosphorylated (e.g., a compound where the amino group in compound (I) or (Ia) is converted into eicosanoylamino, alanylamino, pentylaminocarbonylamino, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofuranylamino, pyrrolidylmethylamino, pivaloyloxymethylamino, or tert-butylamino, etc.); a compound where the hydroxyl group in compound (I) or (Ia) is acylated, alkylated, phosphorylated, or converted into the borate (e.g., a compound where the hydroxyl group in compound (I) or (Ia) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy, etc.); a compound where the carboxyl group in compound (I) or (Ia) is esterified or amidated (e.g., a compound where the carboxyl group in compound (I) or (Ia) is subjected to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, or conversion into the methyl amide, etc.), and the like. These compounds can be produced from compounds (I) and (Ia) according to a well-known method.
Also, the prodrug of compounds (I) or (Ia) may be a compound that is converted into compound (I) or (Ia) under a physiological condition as described in xe2x80x9cIyakuhin No Kaihatu (Development of Drugs)xe2x80x9d, Volume 7, Molecular Design, Hirokawa Shoten, published in 1990; page 163 to page 198.
The agent of the present invention comprising compound (I) or (Ia) shows a high affinity for adenosine receptor, especially for adenosine A3 receptor, while having low toxicity and few side effects. The agent is useful as a safe medicine.
The agent of the present invention comprising compound (I) or (Ia) has a potent adenosine A3 receptor antagonistic activity on mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human, etc.), a good oral absorption, a good metabolical stability, and therefore, it can be used for preventing and/or treating diseases that may be related to adenosine A3 receptor, for example, asthma, allergic disease, inflammation, Addison""s disease, autoimmune hemolytic anemia, Crohn""s disease, psoriasis, rheumatism, central nerve diseases (e.g., cerebrovacular disorders such as haemorrhagia cerebri, cerebral infarction, etc., head injury, spinal injury, cerebral edema, etc.), diabetes, and so on. Preferred is an agent for prevention and/or treatment of central nerve diseases, asthma, allergic disease, etc.
The agent of the present invention comprising compound (I) or (Ia) has low toxicity, and therefore, compound (I) or (Ia) is, either directly as it is or after having been formulated into pharmaceutical compositions along with pharmaceutically acceptable carriers in any per se known manner, for example, into tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquid preparations, injections, suppositories, sustained release preparations, etc., safely administered orally or parenterally (e.g., locally, rectally, intravenously, etc.). In the pharmaceutical composition of the present invention, the amount of compound (I) or (Ia) is from about 0.01 to about 100% by weight based on the total weight of the composition. The dose of the composition varies, depending on the subject to which the composition is administered, the administration route employed, the disorder of the subject, etc. For example, as an adenosine A3 receptor antagonist, oral composition for treating asthma, its dose for adults (body weight ca. 60 kg) may be from about 0.1 to about 30 mg/kg of body weight, preferably from about 1 to about 20 mg/kg of body weight, in terms of the active ingredient (compound (I) or (Ia)), and this may be administered once or divided into several times a day.
Any ordinary organic and inorganic carrier substances that are generally used in formulating medicines are usable as the carriers for formulating the pharmaceutical compositions of the present invention. For example, employable are ordinary excipients, lubricants, binders, disintegrators, etc. for formulating solid preparations; and solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents, etc. for formulating liquid preparations. If desired, further employable are other additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, etc.
The excipients include, for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, etc.
The lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
The binders include, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc.
The disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
The solvents include, for example, water for injections, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.
The solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
The suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.
The isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.
The buffers include, for example, liquid buffers of phosphates, acetates, carbonates, citrates, etc.
The soothing agents include, for example, benzyl alcohol, etc.
The preservatives include, for example, parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
The antioxidants include, for example, sulfites, ascorbic acid, xcex1-tocopherol, etc.